The present invention is concerned with pharmaceutical compositions suitable for the treatment of cancer, and in particular, with pharmaceutical compositions containing vitamin D or a precursor, analogue or metabolite thereof and the use of these compositions in the treatment of a tumor in a subject.
Vitamin D is an isoprenoid compound made up of activated 5-carbon units. The most abundant form of vitamin D is vitamin D3, or cholecalciferol. Vitamin D3 arises from biosynthesis of 7-dehydrocholesterol, an intermediate in cholesterol biosynthesis. Vitamin D3 is metabolised in the liver to 25-hydroxycholecalciferol [25(OH)D3] which is a major form of Vitamin D circulating in the blood compartment 25(OH)D3 is converted by the kidney to produce two principal dihydroxylated metabolites, namely, 1,25-dihydroxycholecalciferol [1,25(OH)2D3] and 24,25-dihydroxycholecalciferol [24R,25(OH)2D3].
1,25(OH)2D3 is the most biologically active naturally occurring form of vitamin D3 and is transported in the bloodstream to its major site of action in the mucosal cells of the intestine, where calcium absorption is stimulated. Thus vitamin D3 may be regarded as a prohormone because it is converted to a metabolite that acts analogously to a steroid hormone. It regulates calcium and phosphorous metabolism particularly in the synthesis of the inorganic matrix of bones.
Systemic administration of high doses of vitamin D3 or its metabolites is limited by the production of hypercalcaemia. This has led to the development of analogues of activated vitamin D (D3) which have a greater effect on cell growth than on calcium metabolism. These compounds have been found to be effective in the inhibition of growth of breast, rectal, colorectal and prostate cancer cells.
We have found that tumors in certain organs, for example, primary and secondary tumors in the liver, can be treated by regional delivery of high concentrations of 1,25(OH)2D3 to the affected organ without giving rise to hypercalcaemia. Applicant""s co-pending International Application No. PCT/AU98/00440, the disclosure of which is incorporated herein by reference, discloses a method for the treatment of liver cancer by means of regional delivery of vitamin D or its metabolite or analogues to the liver.
The effect on tumors is very dose dependent and there is therefore advantage in delivering higher concentrations of vitamin D compounds such as 1,25(OH)2D3. However, the limited solubility of vitamin D and its precursors, analogues and metabolites in a conventional carrier such as water places an upper limit on the concentration of the compound that can be delivered to the organ. Delivery of vitamin D3 intra-arterially in a conventional carrier limits the vitamin D3 concentration in the blood going to the liver to at most 10xe2x88x927 mole per liter.
We have found that very high concentrations of vitamin D compound such as 1,25(OH)2D3 can be achieved by dissolving 1,25(OH)2D3 in a lipid, for example, an iodised or non-iodised oil. A further advantage of using an oil as the carrier for the vitamin D compound is that some oils are concentrated in certain cancers allowing the achievement of very high tumor concentrations of vitamin D3. Moreover, we believe that the use of a lipid as the carrier for the vitamin D compound results in a sustained antiproliferative activity of the vitamin D compound and the compound is retained for considerably longer periods within the tumor.
Accordingly, in a first aspect, the present invention provides a pharmaceutical composition suitable for use in the treatment of cancer cells in an organ by regional delivery of the composition to the organ, the composition including a vitamin D compound and a pharmaceutically acceptable lipid, wherein the concentration of the vitamin D compound in the composition is greater than about 1xc3x9710xe2x88x927 mole per liter.
By the term xe2x80x9cvitamin D compoundxe2x80x9d we include the biologically active and inactive forms of vitamin D. The vitamin D compound may be a precursor, metabolite or analogue of vitamin D. The vitamin D compound may be any analogue having anti-tumor properties. The vitamin D compound maybe cholecalciferol, 25(OH)D3 or 1,25(OH)2D3. Examples of analogues of vitamin D include, but are not restricted to, EB1089, OCT (22-oxa-1,25(OH)2D3), 1xcex125(OH)2, 22,24 diene, 24, 26, 27 trihomo D3, MC903 (calcipotriol) and KH1060, 1,25(OH)2-16-ene 23-yne vitamin D2 and its hexadeutero form. The vitamin D compound may be vitamin D5 or an analogue thereof.
Preferably the concentration of vitamin D compound in the composition of the invention is at least about 1xc3x9710xe2x88x926 mole per liter. The concentration of vitamin D compound may be at least about 1xc3x9710xe2x88x925 mole per liter. The concentration may be at least about 1xc3x9710xe2x88x924 mole per liter. The concentration may be at least 1xc3x9710xe2x88x92""mole per liter. A preferred concentration of the vitamin D compound is about 1xc3x9710xe2x88x926 to 50xc3x9710xe2x88x925 mole per liter.
Preferably the lipid used is one for which the tumor is avid so that high concentrations of the vitamin D compound are delivered to the tumor. To determine whether the tumor being treated is lipid avid or not a-small dose of lipid may be given into the hepatic artery by a percutaneous or surgically placed catheter. A tumor that is not lipid avid is unlikely to benefit from the treatment to the same extent as a tumor that is avid to the the lipid used.
The pharmaceutically acceptable lipid may be an oil. A non-iodised oil is preferred. The non-iodised oil may be any pharmaceutically acceptable oil in which the vitamin D compound is soluble. The non-iodised oil may be a vegetable oil. The oil may be, for example, poppy seed oil, soybean oil, sesame oil, safflower oil, peanut oil, cremophore, Liposyn or Intralipid. The oil may be derived from shark liver oil including squalane and squalene. The lipid may be medium chain triglycerides (MCT).
An iodised oil such as iodised poppy seed oil (lipiodol) can be used, however, the iodine has the effect of making the vitamin D compound more light sensitive.
The lipid may be in the form of an emulsion of these oils prepared with pharmaceutically acceptable emulsifying agents including, but not limited to, natural and synthetic phospholipids, Spans, Tweens or Pluronics,
We have found that very high concentrations of activated vitamin D3 in lipiodol can be achieved. For example, 2 mg of 1,25(OH)2 D3 can be readily dissolved in one ml of iodised poppy seed oil.
Apart from providing a composition that is more effective in the treatment of tumors, the higher concentrations of vitamin D compounds achievable in the composition of the invention provide a reservoir of the vitamin D compound, which is released over time, thus allowing for xe2x80x9cone shotxe2x80x9d administration of the composition.
Furthermore, because the composition of the invention is capable of providing higher concentrations of vitamin D, even non-active forms of vitamin D may be used to treat tumors. Although at low concentrations these non-active forms may not be effective treating tumors, at very high concentrations they may become effective.
The composition of the invention may further include one or more other components. The present composition may contain a component that is capable of increasing vitamin D receptor expression. The composition may include an estrogen, estrogen-like compound or estrogen antagonist. The component may be tamoxifen.
The composition may be used to treat primary or secondary tumors in any organ to which the composition can be administered by regional delivery.
Accordingly, the present invention further extends to a method for the treatment of a tumor in an organ in a subject, the method including regional administration to the organ of a composition in accordance with the present invention.
The regional delivery, may be by means of intra-arterial delivery, for example, by intra-arterial infusion. Alternatively, the composition of the invention may be delivered to the portal vein. The tumor may be a primary or secondary tumor. The organ treated may be the liver, breast, prostate, bone tumor or kidney. The composition of the invention may also be used to treat colorectal cancer or sarcomas. The method and composition of the present invention are particularly suitable for the treatment of hepatoma.
The vitamin D compound may be dissolved in lipid as described above, for example, iodised or non-iodised poppy seed oil to the desired concentration of vitamin D compound.
The method of the invention may be repeated at monthly, or other, intervals. It will be readily apparent that the composition and method of the present invention provide the capability of delivering very high local concentration of vitamin D substance delivered by the composition of the present invention will achieve tumor control and whilst avoiding hypercalcaemia.
In order to more fully describe the invention we provide the following non-limiting examples.